scholarly journals Desmin is a modifier of dystrophic muscle features in Mdx mice

2019 ◽  
Author(s):  
Arnaud Ferry ◽  
Julien Messéant ◽  
Ara Parlakian ◽  
Mégane Lemaitre ◽  
Pauline Roy ◽  
...  
Keyword(s):  
Neuromuscular Disease ◽  
Muscle Hypertrophy ◽  
Force Production ◽  
Muscle Performance ◽  
Mdx Mice ◽  
Force Transmission ◽  
Dystrophic Muscle ◽  
Adeno Associated Virus ◽  
Dystrophin Deficiency ◽  
Insight Into

AbstractDuchenne muscular dystrophy (DMD) is a severe neuromuscular disease, caused by dystrophin deficiency. Desmin is like dystrophin associated to costameric structures bridging sarcomeres to extracellular matrix that are involved in force transmission and skeletal muscle integrity. In the present study, we wanted to gain further insight into the roles of desmin which expression is increased in the muscle from the mouse Mdx DMD model. We show that a deletion of the desmin gene (Des) in Mdx mice (DKO, Mdx:desmin-/-) induces a marked worsening of the weakness (reduced maximal force production) as compared to Mdx mice. Fragility (higher susceptibility to contraction-induced injury) was also aggravated and fatigue resistance was reduced in DKO mice. Moreover, in contrast to Mdx mice, the DKO mice did not undergo a muscle hypertrophy because of smaller and less numerous fibers, with reduced percentage of centronucleated fibres. Interestingly, Desmin cDNA transfer with adeno-associated virus in 1-month-old DKO mice and newborn Mdx mice improved muscle weakness. Overall, desmin plays important and beneficial roles on muscle performance, fragility and remodelling in dystrophic Mdx mice.

scholarly journals Improvement of Endurance of DMD Animal Model Using Natural Polyphenols

2015 ◽  
Vol 2015 ◽  
pp. 1-17 ◽  
Author(s):  
Clementina Sitzia ◽  
Andrea Farini ◽  
Federica Colleoni ◽  
Francesco Fortunato ◽  
Paola Razini ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Genetic Defect ◽  
Premature Death ◽  
Mdx Mice ◽  
Dystrophic Muscle ◽  
Muscle Fibrosis ◽  
Natural Polyphenols ◽  
Dystrophin Deficiency ◽  
Force Reduction ◽  
Muscular Architecture

Duchenne muscular dystrophy (DMD), the most common form of muscular dystrophy, is characterized by muscular wasting caused by dystrophin deficiency that ultimately ends in force reduction and premature death. In addition to primary genetic defect, several mechanisms contribute to DMD pathogenesis. Recently, antioxidant supplementation was shown to be effective in the treatment of multiple diseases including muscular dystrophy. Different mechanisms were hypothesized such as reduced hydroxyl radicals, nuclear factor-κB deactivation, and NO protection from inactivation. Following these promising evidences, we investigated the effect of the administration of a mix of dietary natural polyphenols (ProAbe) on dystrophic mdx mice in terms of muscular architecture and functionality. We observed a reduction of muscle fibrosis deposition and myofiber necrosis together with an amelioration of vascularization. More importantly, the recovery of the morphological features of dystrophic muscle leads to an improvement of the endurance of treated dystrophic mice. Our data confirmed that ProAbe-based diet may represent a strategy to coadjuvate the treatment of DMD.

scholarly journals Prox1 gene transfer combined with voluntary exercise improves dystrophic muscle fragility in Mdx mice

2020 ◽  
Author(s):  
Alexandra Monceau ◽  
Clément Delacroix ◽  
Mégane Lemaitre ◽  
Onnik Agbulut ◽  
Denis Furling ◽  
...  
Keyword(s):  
Force Production ◽  
Voluntary Exercise ◽  
Mdx Mice ◽  
Muscle Fibres ◽  
Dystrophic Muscle ◽  
Muscle Weight ◽  
Lengthening Contractions ◽  
Beneficial Effects ◽  
Voluntary Running ◽  
Slow Muscle Fibres

Abstract Background Voluntary exercise can improve skeletal muscle fragility, i.e. higher susceptibility to contraction induced-injury, as shown by a greater force drop following lengthening contractions, in the dystrophic Mdx mice as compared to healthy mice with dystrophin. This beneficial effect is related to the activation of the calcineurin activation. Unfortunately, voluntary running only partly rescued fragility, so it would be interesting to combined the effects of exercise, for example, with those of others treatments activating the calcineurin pathway and promoting slow and more oxidative fibres. This is of particular interest because slow muscle fibres are apparently less affected and genetic or pharmacological treatments promoting slow and more oxidative fibres are been shown to be beneficial in the Mdx mice. Methods Here, we tested whether voluntary exercise (1 month of running in a wheel) combined with Prospero-related homeobox factor 1 gene ( Prox1) transfer would better improve functional dystrophic features in Mdx mice as compared to the voluntary exercise single approach. Prox1 is known to promote the promotion of slow contractile gene program in healthy muscle. Results We found that Prox1 transfer promoted slower molecular and functional contractile features in both voluntary exercised and sedentary Mdx mice. However, it improved fragility only in exercised Mdx mice. Moreover, Prox1 transfer reduced absolute maximal force production by causing reduction in muscle weight in both exercised and sedentary Mdx mice. Conclusion In conclusion, our results indicate that the beneficial effects of voluntary exercise and Prox1 transfer on fragility are additive in Mdx mice.

scholarly journals Indices of Defective Autophagy in Whole Muscle and Lysosome Enriched Fractions From Aged D2-mdx Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Swathy Krishna ◽  
Hannah R. Spaulding ◽  
Tiffany S. Quindry ◽  
Matthew B. Hudson ◽  
John C. Quindry ◽  
...  
Keyword(s):  
Muscle Protein ◽  
Muscle Disease ◽  
Mdx Mice ◽  
Autophagosome Formation ◽  
Dystrophic Muscle ◽  
Dystrophin Deficiency ◽  
Gastrocnemius Muscles ◽  
Dystrophin Protein ◽  
Whole Muscle ◽  
Muscle Specificity

Duchenne muscular dystrophy (DMD) is a fatal, progressive muscle disease caused by the absence of functional dystrophin protein. Previous studies in mdx mice, a common DMD model, identified impaired autophagy with lysosomal insufficiency and impaired autophagosomal degradation as consequences of dystrophin deficiency. Thus, we hypothesized that lysosomal abundance would be decreased and degradation of autophagosomes would be impaired in muscles of D2-mdx mice. To test this hypothesis, diaphragm and gastrocnemius muscles from 11 month-old D2-mdx and DBA/2J (healthy) mice were collected. Whole muscle protein from diaphragm and gastrocnemius muscles, and protein from a cytosolic fraction (CF) and a lysosome-enriched fraction (LEF) from gastrocnemius muscles, were isolated and used for western blotting. Initiation of autophagy was not robustly activated in whole muscle protein from diaphragm and gastrocnemius, however, autophagosome formation markers were elevated in dystrophic muscles. Autophagosome degradation was impaired in D2-mdx diaphragms but appeared to be maintained in gastrocnemius muscles. To better understand this muscle-specific distinction, we investigated autophagic signaling in CFs and LEFs from gastrocnemius muscles. Within the LEF we discovered that the degradation of autophagosomes was similar between groups. Further, our data suggest an expanded, though impaired, lysosomal pool in dystrophic muscle. Notably, these data indicate a degree of muscle specificity as well as model specificity with regard to autophagic dysfunction in dystrophic muscles. Stimulation of autophagy in dystrophic muscles may hold promise for DMD patients as a potential therapeutic, however, it will be critical to choose the appropriate model and muscles that most closely recapitulate findings from human patients to further develop these therapeutics.

Branched fibers in dystrophic mdx muscle are associated with a loss of force following lengthening contractions

2007 ◽  
Vol 293 (3) ◽  
pp. C985-C992 ◽  
Author(s):  
S. Chan ◽  
S. I. Head ◽  
J. W. Morley
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Extensor Digitorum Longus ◽  
Muscle Fibers ◽  
Force Production ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Dystrophic Muscle ◽  
Lengthening Contractions ◽  
Fast Twitch

We demonstrated that the susceptibility of skeletal muscle to injury from lengthening contractions in the dystrophin-deficient mdx mouse is directly linked with the extent of fiber branching within the muscles and that both parameters increase as the mdx animal ages. We subjected isolated extensor digitorum longus muscles to a lengthening contraction protocol of 15% strain and measured the resulting drop in force production (force deficit). We also examined the morphology of individual muscle fibers. In mdx mice 1–2 mo of age, 17% of muscle fibers were branched, and the force deficit of 7% was not significantly different from that of age-matched littermate controls. In mdx mice 6–7 mo of age, 89% of muscle fibers were branched, and the force deficit of 58% was significantly higher than the 25% force deficit of age-matched littermate controls. These data demonstrated an association between the extent of branching and the greater vulnerability to contraction-induced injury in the older fast-twitch dystrophic muscle. Our findings demonstrate that fiber branching may play a role in the pathogenesis of muscular dystrophy in mdx mice, and this could affect the interpretation of previous studies involving lengthening contractions in this animal.

scholarly journals Autophagy in the heart is enhanced and independent of disease progression in mus musculus dystrophinopathy models

2019 ◽  
Vol 8 ◽  
pp. 204800401987958
Author(s):  
HR Spaulding ◽  
C Ballmann ◽  
JC Quindry ◽  
MB Hudson ◽  
JT Selsby
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Disease Progression ◽  
Gene Mutations ◽  
Dystrophin Gene ◽  
Mdx Mice ◽  
Dystrophin Deficiency ◽  
Muscle Wasting Disease ◽  
Dystrophin Protein

Background Duchenne muscular dystrophy is a muscle wasting disease caused by dystrophin gene mutations resulting in dysfunctional dystrophin protein. Autophagy, a proteolytic process, is impaired in dystrophic skeletal muscle though little is known about the effect of dystrophin deficiency on autophagy in cardiac muscle. We hypothesized that with disease progression autophagy would become increasingly dysfunctional based upon indirect autophagic markers. Methods Markers of autophagy were measured by western blot in 7-week-old and 17-month-old control (C57) and dystrophic (mdx) hearts. Results Counter to our hypothesis, markers of autophagy were similar between groups. Given these surprising results, two independent experiments were conducted using 14-month-old mdx mice or 10-month-old mdx/Utrn± mice, a more severe model of Duchenne muscular dystrophy. Data from these animals suggest increased autophagosome degradation. Conclusion Together these data suggest that autophagy is not impaired in the dystrophic myocardium as it is in dystrophic skeletal muscle and that disease progression and related injury is independent of autophagic dysfunction.

scholarly journals Treatment with rGDF11 does not improve the dystrophic muscle pathology of mdx mice

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Fabrizio Rinaldi ◽  
Yu Zhang ◽  
Ricardo Mondragon-Gonzalez ◽  
Jeffrey Harvey ◽  
Rita C. R. Perlingeiro
Keyword(s):  
Muscle Pathology ◽  
Mdx Mice ◽  
Dystrophic Muscle

scholarly journals Early metabolic changes measured by 1H MRS in healthy and dystrophic muscle after injury

2012 ◽  
Vol 113 (5) ◽  
pp. 808-816 ◽  
Author(s):  
Su Xu ◽  
Stephen J. P. Pratt ◽  
Espen E. Spangenburg ◽  
Richard M. Lovering
Keyword(s):  
Skeletal Muscle ◽  
Muscle Injury ◽  
Tibialis Anterior Muscle ◽  
Metabolic Changes ◽  
Mdx Mice ◽  
Resonance Spectroscopy ◽  
Dystrophic Muscle ◽  
1H Mrs ◽  
Skeletal Muscle Injury

Skeletal muscle injury is often assessed by clinical findings (history, pain, tenderness, strength loss), by imaging, or by invasive techniques. The purpose of this work was to determine if in vivo proton magnetic resonance spectroscopy (1H MRS) could reveal metabolic changes in murine skeletal muscle after contraction-induced injury. We compared findings in the tibialis anterior muscle from both healthy wild-type (WT) muscles (C57BL/10 mice) and dystrophic ( mdx mice) muscles (an animal model for human Duchenne muscular dystrophy) before and after contraction-induced injury. A mild in vivo eccentric injury protocol was used due to the high susceptibility of mdx muscles to injury. As expected, mdx mice sustained a greater loss of force (81%) after injury compared with WT (42%). In the uninjured muscles, choline (Cho) levels were 47% lower in the mdx muscles compared with WT muscles. In mdx mice, taurine levels decreased 17%, and Cho levels increased 25% in injured muscles compared with uninjured mdx muscles. Intramyocellular lipids and total muscle lipid levels increased significantly after injury but only in WT. The increase in lipid was confirmed using a permeable lipophilic fluorescence dye. In summary, loss of torque after injury was associated with alterations in muscle metabolite levels that may contribute to the overall injury response in mdx mice. These results show that it is possible to obtain meaningful in vivo 1H MRS regarding skeletal muscle injury.

Effects of hypoxia and hypercapnia on geniohyoid contractility and endurance

1991 ◽  
Vol 71 (2) ◽  
pp. 709-715 ◽  
Author(s):  
R. J. Salmone ◽  
E. Van Lunteren
Keyword(s):  
Force Production ◽  
Upper Airway ◽  
Muscle Performance ◽  
Severe Hypoxia ◽  
Force Frequency ◽  
Force Output ◽  
Frequency Curve ◽  
Dilator Muscle ◽  
Index Ratio ◽  
Mild Hypoxia

Sleep apnea and other respiratory diseases produce hypoxemia and hypercapnia, factors that adversely affect skeletal muscle performance. To examine the effects of these chemical alterations on force production by an upper airway dilator muscle, the contractile and endurance characteristics of the geniohyoid muscle were examined in situ during severe hypoxia (arterial PO2 less than 40 Torr), mild hypoxia (PO2 45–65 Torr), and hypercapnia (PCO2 55–80 Torr) and compared with hyperoxic-normocapnic conditions in anesthetized cats. Muscles were studied at optimal length, and contractile force was assessed in response to supramaximal electrical stimulation of the hypoglossal nerve (n = 7 cats) or geniohyoid muscle (n = 2 cats). There were no significant changes in the twitch kinetics or force-frequency curve of the geniohyoid muscle during hypoxia or hypercapnia. However, the endurance of the geniohyoid, as reflected in the fatigue index (ratio of force at 2 min to initial force in response to 40-Hz stimulation at a duty cycle 0.33), was significantly reduced by severe hypoxia but not by hypercapnia or mild hypoxia. In addition, the downward shift in the force-frequency curve after the repetitive stimulation protocol was greater during hypoxia than hyperoxia, especially at higher frequencies. In conclusion, the ability of the geniohyoid muscle to maintain force output during high levels of activation is adversely affected by severe hypoxia but not mild hypoxia or hypercapnia. However, none of these chemical perturbations affected muscle contractility acutely.

scholarly journals Dissipation of contractile forces: the missing piece in cell mechanics

2017 ◽  
Vol 28 (14) ◽  
pp. 1825-1832 ◽  
Author(s):  
Laetitia Kurzawa ◽  
Benoit Vianay ◽  
Fabrice Senger ◽  
Timothée Vignaud ◽  
Laurent Blanchoin ◽  
...  
Keyword(s):  
Cell Mechanics ◽  
Force Production ◽  
Traction Force ◽  
Structural Rearrangements ◽  
Force Transmission ◽  
Traction Forces ◽  
Cell Traction Forces ◽  
Cell Traction ◽  
Contractile Forces ◽  
Fiber Contraction

Mechanical forces are key regulators of cell and tissue physiology. The basic molecular mechanism of fiber contraction by the sliding of actin filament upon myosin leading to conformational change has been known for decades. The regulation of force generation at the level of the cell, however, is still far from elucidated. Indeed, the magnitude of cell traction forces on the underlying extracellular matrix in culture is almost impossible to predict or experimentally control. The considerable variability in measurements of cell-traction forces indicates that they may not be the optimal readout to properly characterize cell contractile state and that a significant part of the contractile energy is not transferred to cell anchorage but instead is involved in actin network dynamics. Here we discuss the experimental, numerical, and biological parameters that may be responsible for the variability in traction force production. We argue that limiting these sources of variability and investigating the dissipation of mechanical work that occurs with structural rearrangements and the disengagement of force transmission is key for further understanding of cell mechanics.

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